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Volume 40 Issue 8
Aug.  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(8): 1627-1632

Liver disease phenotypes and clinical features of patients with different genotypes of Wilson’s disease

DOI: 10.12449/JCH240819
  • 1.

    Peking University 302 Clinical Medical School，Beijing 100191，China

  • 2.

    Department of Liver Diseases，The Fifth Medical Center of Chinese PLA General Hospital，Beijing 100039，China

Research funding:

Captial Medical Development Fund (2022-1-2182)

More Information
  • Corresponding author: ZHANG Min， gcmw2001@163.com （ORCID： 0000-0003-2497-6748）
  • Received Date: 2023-11-13
  • Accepted Date: 2023-12-25
  • Published Date: 2024-08-25
    Abstract
  •   Objective  To investigate the liver disease phenotypes and clinical features of patients with different genotypes of Wilson’s disease （WD）.  Methods  A retrospective analysis was performed for 163 patients with WD who were diagnosed and underwent genetic testing in The Fifth Medical Center of Chinese PLA General Hospital from August 2008 to June 2023， and clinical manifestations， laboratory examination， pathological examination， imaging examination， and ATP7B genetic testing results were collected. According to ATP7B gene mutation， the patients were divided into groups as follows： R778L mutation group and non-R778L mutation group； P992L mutation group and non-P992L mutation group； truncation mutation group and non-truncation mutation group. Liver disease phenotypes and clinical features were analyzed for the patients with c.2333G>T/p.R778L mutation （R778L mutation）， c.2975C>T/p.P992L mutation （P992L mutation）， and truncation mutation of the ATP7B gene. The Mann-Whitney U test or the Kruskal-Wallis H test was used for comparison of continuous data between groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups.  Results  The 163 patients with WD had varying severities of liver disease phenotypes， among whom 121 （74.23%） were diagnosed with chronic liver disease， 36 （22.09%） were diagnosed with decompensated cirrhosis， and 6 （3.68%） were diagnosed with fulminant WD， and in addition， there were 5 patients （2 with chronic liver disease and 3 with decompensated cirrhosis） with neurological abnormalities. For the 163 patients with WD， R778L mutation （with an allele frequency of 28.2%） was the most common mutation in the ATP7B gene， followed by P992L mutation （with an allele frequency of 12.6%）， and truncation mutation showed an allele frequency of 11.0%. There was no significant difference in the distribution of the three mutations across different liver disease phenotypes （P>0.05）. The R778L mutation group had a significantly lower level of ceruloplasmin （CP） than the non-R778L mutation group ［0.04 （0.02‍ ‍—‍ ‍0.08） g/L vs 0.08 （0.03‍ ‍—‍ ‍0.13） g/L， Z=-2.889， P=0.004］. Compared with the non-P992L mutation group， the P992L mutation group had significantly higher levels of alanine aminotransferase ［135.0 （80.5‍ ‍—‍ ‍237.0） U/L vs 80.5 （36.0‍ ‍—‍ ‍173.3） U/L， Z=2.684， P=0.007］ and aspartate aminotransferase ［121.4 （77.0‍ ‍—‍ ‍195.0） U/L vs 84.0 （39.0‍ ‍—‍ ‍123.3） U/L， Z=3.388， P<0.001］. Compared with the non-truncation mutation group， the truncation mutation group had significantly lower levels of CP ［0.03 （0.02‍ ‍—‍ ‍0.08） g/L vs 0.06 （0.03‍ ‍—‍ ‍0.11） g/L， Z=-3.136， P=0.002］ and serum copper ［3.20 （2.15‍ ‍—‍ ‍5.00） mg/L vs 4.20 （2.60‍ ‍—‍ ‍7.50） mg/L， Z=-2.296， P=0.025］.  Conclusion  R778L mutation， P992L mutation and truncation mutation are not associated with liver disease phenotype in WD patients； however， R778L mutation is associated with a lower level of CP， P992L mutation is associated with higher levels of ALT and AST， and truncation mutation is associated with lower levels of CP and serum copper.

     

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    • References(26)
  • [1]
    MALIPATI AEKJ, KAIDIRIYA KEB, XU L, et al. Research advances in the pathogenesis, phenotype-genotype relationship, and pharmacotherapy of hepatolenticular degeneration[J]. J Clin Hepatol, 2023, 39( 6): 1497- 1504. DOI: 10.3969/j.issn.1001-5256.2023.06.037.

    玛力帕提·艾尔肯江, 凯迪日亚·库尔班, 徐玲, 等. 肝豆状核变性发病机制、临床表型-基因型关系及药物治疗研究进展[J]. 临床肝胆病杂志, 2023, 39( 6): 1497- 1504. DOI: 10.3969/j.issn.1001-5256.2023.06.037.
    [2]
    FERENCI P, STREMMEL W, CZŁONKOWSKA A, et al. Age and sex but not ATP7B genotype effectively influence the clinical phenotype of Wilson disease[J]. Hepatology, 2019, 69( 4): 1464- 1476. DOI: 10.1002/hep.30280.
    [3]
    CAI L, HUANG XT, YE Y, et al. Role of gender and age in features of Wilson’s disease[J]. Front Neurol, 2023, 14: 1176946. DOI: 10.3389/fneur.2023.1176946.
    [4]
    ROBERTS EA, SCHILSKY ML. Current and emerging issues in Wilson’s disease[J]. N Engl J Med, 2023, 389( 10): 922- 938. DOI: 10.1056/NEJMra1903585.
    [5]
    DONG Y, NI W, CHEN WJ, et al. Spectrum and classification of ATP7B variants in a large cohort of Chinese patients with Wilson’s disease guides genetic diagnosis[J]. Theranostics, 2016, 6( 5): 638- 649. DOI: 10.7150/thno.14596.
    [6]
    DAS S, MOHAMMED A, MANDAL T, et al. Polarized trafficking and copper transport activity of ATP7B: A mutational approach to establish genotype-phenotype correlation in Wilson disease[J]. Hum Mutat, 2022, 43( 10): 1408- 1429. DOI: 10.1002/humu.24428.
    [7]
    ZHANG TH, MAO ZQ. Clinical characteristics and gene analysis of hepatolenticular degeneration in children: A report of 70 cases[J]. Chin J Pract Pediatr, 2022, 37( 2): 135- 139. DOI: 10.19538/j.ek2022020614.

    张天鹤, 毛志芹. 儿童肝豆状核变性的临床特点及基因分析(附70例报告)[J]. 中国实用儿科杂志, 2022, 37( 2): 135- 139. DOI: 10.19538/j.ek2022020614.
    [8]
    XUE ZR, CHEN HY, YU L, et al. A systematic review and meta-analysis of the R778L mutation in ATP7B with Wilson disease in China[J]. Pediatr Neurol, 2023, 145: 135- 147. DOI: 10.1016/j.pediatrneurol.2023.04.026.
    [9]
    ZHANG SJ, YANG WM, LI X, et al. Clinical and genetic characterization of a large cohort of patients with Wilson’s disease in China[J]. Transl Neurodegener, 2022, 11( 1): 13. DOI: 10.1186/s40035-022-00287-0.
    [10]
    OKADA T, SHIONO Y, KANEKO Y, et al. High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson’s disease[J]. Scand J Gastroenterol, 2010, 45( 10): 1232- 1237. DOI: 10.3109/00365521.2010.492527.
    [11]
    MERLE U, WEISS KH, EISENBACH C, et al. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease[J]. BMC Gastroenterol, 2010, 10: 8. DOI: 10.1186/1471-230X-10-8.
    [12]
    FERENCI P, CACA K, LOUDIANOS G, et al. Diagnosis and phenotypic classification of Wilson disease[J]. Liver Int, 2003, 23( 3): 139- 142. DOI: 10.1034/j.1600-0676.2003.00824.x.
    [13]
    ROZEN S, SKALETSKY H. Primer3 on the WWW for general users and for biologist programmers[J]. Methods Mol Biol, 2000, 132: 365- 386. DOI: 10.1385/1-59259-192-2: 365.
    [14]
    JI L, ZHANG Y, KONG L, et al. Clinical features of Wilson’s disease: An analysis of 83 cases[J]. J Clin Hepatol, 2022, 38( 8): 1843- 1846. DOI: 10.3969/j.issn.1001-5256.2022.08.023.

    纪雷, 张莹, 孔丽, 等. 83例肝豆状核变性患者的临床特征分析[J]. 临床肝胆病杂志, 2022, 38( 8): 1843- 1846. DOI: 10.3969/j.issn.1001-5256.2022.08.023.
    [15]
    European Association for study of Liver. EASL clinical practice guidelines: Wilson’s disease[J]. J Hepatol, 2012, 56( 3): 671- 685. DOI: 10.1016/j.jhep.2011.11.007.
    [16]
    CHOE EJ, CHOI JW, KANG MJ, et al. A population-based epidemiology of Wilson’s disease in South Korea between 2010 and 2016[J]. Sci Rep, 2020, 10( 1): 14041. DOI: 10.1038/s41598-020-70976-1.
    [17]
    OKADA T, SHIONO Y, HAYASHI H, et al. Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson’s disease[J]. Hum Mutat, 2000, 15( 5): 454- 462. DOI: 3.0.CO;2-J">10.1002/(SICI)1098-1004(200005)15: 5<454: AID-HUMU7>3.0.CO;2-J.
    [18]
    ESPINÓS C, FERENCI P. Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice?[J]. JHEP Rep, 2020, 2( 4): 100114. DOI: 10.1016/j.jhepr.2020.100114.
    [19]
    LIU XQ, ZHANG YF, LIU TT, et al. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease[J]. World J Gastroenterol, 2004, 10( 4): 590- 593. DOI: 10.3748/wjg.v10.i4.590.
    [20]
    LALIOTI V, SANDOVAL I, CASSIO D, et al. Molecular pathology of Wilson’s disease: A brief[J]. J Hepatol, 2010, 53( 6): 1151- 1153. DOI: 10.1016/j.jhep.2010.07.008.
    [21]
    HUSTER D, HOPPERT M, LUTSENKO S, et al. Defective cellular localization of mutant ATP7B in Wilson’s disease patients and hepatoma cell lines[J]. Gastroenterology, 2003, 124( 2): 335- 345. DOI: 10.1053/gast.2003.50066.
    [22]
    FANNI D, GEROSA C, NURCHI VM, et al. Copper-induced epigenetic changes shape the clinical phenotype in Wilson’s disease[J]. Curr Med Chem, 2021, 28( 14): 2707- 2716. DOI: 10.2174/0929867327666200730214757.
    [23]
    KIEFFER DA, MEDICI V. Wilson disease: At the crossroads between genetics and epigenetics-a review of the evidence[J]. Liver Res, 2017, 1( 2): 121- 130. DOI: 10.1016/j.livres.2017.08.003.
    [24]
    SCHIEFERMEIER M, KOLLEGGER H, MADL C, et al. The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson’s disease[J]. Brain, 2000, 123 Pt 3: 585- 590. DOI: 10.1093/brain/123.3.585.
    [25]
    STUEHLER B, REICHERT J, STREMMEL W, et al. Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients[J]. J Mol Med(Berl), 2004, 82( 9): 629- 634. DOI: 10.1007/s00109-004-0557-9.
    [26]
    HUANG YZ, ZHANG M. Advances in molecular mechanism of ATP7B gene mutation in hepatolenticular degeneration[J]. Chin Hepatol, 2023, 28( 7): 866- 872. DOI: 10.14000/j.cnki.issn.1008-1704.2023.07.019.

    黄元志, 张敏. 肝豆状核变性ATP7B基因突变的分子机制研究进展[J]. 肝脏, 2023, 28( 7): 866- 872. DOI: 10.14000/j.cnki.issn.1008-1704.2023.07.019.
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